Jin Z, Xiang C, Cai Q, Wei X, He J. Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies. Ann Rheum 2013. doi: 10.1136/annrheumdis-2013-203323
Objective To summarise the evidence regarding the dose-response association between alcohol consumption and risk of rheumatoid arthritis (RA).
Method Studies were identified from search of MEDLINE, Embase and Web of Science databases between 1 January 1946 and 10 April 2013, and from review of the conference abstracts and the reference lists of retrieved articles. Prospective studies that reported relative risks (RRs) with 95% CIs for the association between alcohol consumption and the risk of RA were included. Results from individual studies were pooled using a dose-response meta-analysis.
Results Up to 10 April 2013, 8 prospective studies contained 195 029 participants and 1878 RA cases were included. The results indicated that low to moderate alcohol consumption yielded a preventive effect on RA development (RR: 0.86; 95% CI 0.78 to 0.94), and provided some evidence of a non-linear relationship between alcohol consumption and risk of RA. Dose-response meta-analysis of the study data revealed that compared with that for no alcohol consumption, the adjusted RR was 0.93 (95% CI 0.88 to 0.98) for 3 g/day of alcohol consumption, 0.86 (95% CI 0.76 to 0.97) for 9 g/day, 0.88 (95% CI 0.78 to 0.99) for 12 g/day, 0.91 (95% CI 0.81 to 1.03) for 15 g/day, and 1.28 (95% CI 0.94 to 1.73) for 30 g/day. Subgroup analysis indicated that women who had low to moderate alcohol consumption had a 19% reduction in RA risk. Regardless of sex, a consistent low to moderate alcohol consumption for a period of at least 10 years was found to have a 17% reduction in RA risk.
Conclusions Low to moderate alcohol consumption is inversely associated with the development of RA in a manner that appears to be dose-dependent, time-dependent and sex-dependent. Large prospective studies that investigate gene-environment interactions are required to further clarify the aetiology of RA.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic, destructive, debilitating arthritis that affects ~1% of the adult population. A number of case-control studies have shown that moderate drinking is associated with lower occurrence and severity of RA, but few prospective cohort studies have an adequate number of cases to test the association of alcohol consumption with the development of RA. The present meta-analysis, based on prospective data from almost 200,000 subjects in 5 cohort studies and 3 nested case-control studies, relates alcohol to the occurrence of RA in 1,878 subjects.
The key findings of this study are that, overall, subjects reporting low to moderate alcohol consumption (< 15 g/d) had a lower risk of RA (RR: 0.86; 95% CI 0.78, 0.94) than abstainers, with evidence of a “J-shaped” curve. Further, subgroup analysis indicated that alcohol consumption of 15 g/day or less for a period of at least 10 years was found to be associated with a 17% reduction in RA risk for both men and women.
For RA, there is prior evidence that moderate drinking may reduce its occurrence. For example, in 2012 Di Giuseppe et al (Di Giuseppe D, Alfredsson L, Bottai M, Askling J, Wolk A. Long term alcohol intake and risk of rheumatoid arthritis in women: a population based cohort study. BMJ 2012;345:e4230 doi: 10.1136/bmj.e4230) reported results of a follow-up study of more than 34,000 women in Sweden. That study showed that moderate drinkers, in comparison with abstainers, were at significantly lower risk of developing RA. In that study, women who consumed at least 4 drinks per week (with a drink being defined as containing 15 grams of alcohol) had 37% lower risk of developing RA than subjects reporting never drinking or consuming less than 1 drink/week. (The review of that paper by our Forum is available at www.bu.edu/alcohol-forum/critique-084.).
Forum member Van Velden noted: “It is interesting to note that alcohol has a positive effect on RA, in contrast to smoking which is the most important environmental factor in RA. This disease has the same U-shaped association with daily alcohol consumption as in the case of osteoporosis. Genetic factors play a very important role in RA, and we need to establish correlations with environmental triggers in the management of this serious immunological disorder.”“
Reviewer Svilaas pointed out that while the main results show a greater effect of alcohol among women, it is important to note the authors’ statement that “Regardless of sex, a consistent low to moderate alcohol consumption for a period of at least 10 years was found to have a 17% reduction in RA risk.”
Possible mechanisms: Down regulation of the immune response and a decrease in pro-inflammatory cytokines is the probable mechanism of alcohol’s effect on the risk of RA. Reviewer Skovenborg states: “The biological plausibility is supported by the findings in several studies of a negative association between alcohol consumption and other autoimmune diseases such as systemic lupus erythematosus (Clin Rheumatol 2008;27:1557-63), autoimmune diabetes mellitus (Diabet Med 2013;30:56-64), autoimmune hypothyroidism (European Journal of Endocrinology 2012;167:483-90) and Graves’ hyperthyroidism (Clinical Endocrinology 2013;79:111-119). The most convincing evidence to date that alcohol consumption might prevent the development of destructive arthritis comes from the laboratory studies on mice (not mentioned by the authors): (Jonsson I-M et al. Ethanol prevents development of destructive arthritis. PNAS 2007;104:258-63). And just to end the story with some anecdotal evidence: wine has been used as treatment of rheumatoid skin ulcerations (Arthritis and Rheumatism 1983;26:934-35).
Forum member Ursini stated: “The emerging biological target of alcohol, better when assumed as wine, similarly to the long series of redox active phytochemicals present in fruit and vegetables, is the modulation of the inflammatory response. The concept of nutritional hormesis (including xeno-hormesis and para-hormesis) operating by redox transitions and affecting the nucleophilic tone – in turn preventing biological damage by excess of response to an injury – is going to eventually bridge the gap between basic science and epidemiological evidence.
Reviewer Ellison pointed out that the Nurses’ Health Study has provided additional epidemiologic evidence for biologic plausibility for an inverse association between alcohol and RA. In a study by Lu et al (Lu B, Solomon DH, Costenbader KH, et al. Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis. Arthritis Rheum 2010;62:3554–9), it was found from stored blood samples that there was a “U-shaped” association between alcohol intake and IL-6 levels for subjects who subsequently developed evidence of RA.
Moderate alcohol intake, compared with abstinence, has been related to lower inflammatory markers and a reduced risk of many auto-immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmure diabetes, and Graves hyperthyroidism. The present large meta-analysis relating alcohol to RA includes data from 5 prospective cohort studies and 3 nested case-control studies. Their analyses are based on prospective data from a total of almost 200,000 subjects, among whom 1,878 developed RA.
This meta-analysis concludes that low to moderate alcohol consumption is inversely associated with the development of RA. It suggests a “J-shaped” curve, with a lowered risk for an average intake of up to 15 g of alcohol (about 1 to 1 ½ typical drinks), in comparison with non-drinkers, and an increased risk for heavier drinking. While the immediate effects were greater for women in this study, for long-term effects the authors noted that “Regardless of sex, a consistent low to moderate alcohol consumption for a period of at least 10 years was found to have a 17% reduction in RA risk.”
Beneficial effects of alcohol on indices of inflammation have been shown repeatedly. The probable mechanism of alcohol’s effect on the risk of RA is down regulation of the immune response and a decrease in pro-inflammatory cytokines.
Reference: Jin Z, Xiang C, Cai Q, Wei X, He J. Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies. Ann Rheum 2013. doi: 10.1136/annrheumdis-2013-203323
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The following members of the International Scientific Forum on Alcohol Research made contributions to this review:
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA
Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy;
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA